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A multicenter, randomized study of decitabine as epigenetic priming with induction chemotherapy in children with AML.

ABSTRACT: Decitabine is a deoxycytidine nucleoside derivative inhibitor of DNA-methyltransferases, which has been studied extensively and is approved for myelodysplastic syndrome in adults but with less focus in children. Accordingly, we conducted a phase 1 multicenter, randomized, open-label study to evaluate decitabine pre-treatment before standard induction therapy in children with newly diagnosed AML to assess safety and tolerability and explore a number of biologic endpoints.Twenty-four patients were fully assessable for all study objectives per protocol (10 in Arm A = epigenetic priming induction, 14 in Arm B = standard induction). All patients experienced neutropenia and thrombocytopenia. The most common grade 3 and 4 non-hematologic adverse events observed were gastrointestinal toxicities and hypophosphatemia. Plasma decitabine PK were similar to previously reported adult data. Overall CR/CRi was similar for the two arms. MRD negativity at end-induction was 85% in Arm A versus 67% in Arm B patients. DNA methylation measured in peripheral blood over the course of treatment tracked with blast clearance and matched marrow aspirates at day 0 and day 21. Unlike end-induction marrow analyses, promoter methylation in blood identified an apparent reversal of response in the lone treatment failure, 1 week prior to the patient's marrow aspirate confirming non-response. Decitabine-induced effects on end-induction (day 35-43 following initiation of treatment) marrows in Arm A were reflected by changes in DNA methylation in matched paired marrow diagnostic aspirates.This first-in-pediatrics trial demonstrates that decitabine prior to standard combination chemotherapy is feasible and well tolerated in children with newly diagnosed AML. Pre-treatment with decitabine may represent a newer therapeutic option for pediatric AML, especially as it appears to induce important epigenetic alterations. The novel biological correlates studied in this trial offer a clinically relevant window into disease progression and remission. Additional studies are needed to definitively assess whether decitabine can enhance durability responses in children with AML.NCT01177540.

SUBMITTER: Gore L

PROVIDER: S-EPMC5629751 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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A multicenter, randomized study of decitabine as epigenetic priming with induction chemotherapy in children with AML.

Gore Lia L Triche Timothy J TJ Farrar Jason E JE Wai Daniel D Legendre Christophe C Gooden Gerald C GC Liang Winnie S WS Carpten John J Lee David D Alvaro Frank F Macy Margaret E ME Arndt Carola C Barnette Philip P Cooper Todd T Martin Laura L Narendran Aru A Pollard Jessica J Meshinchi Soheil S Boklan Jessica J Arceci Robert J RJ Salhia Bodour B

Clinical epigenetics 20171005

<h4>Background</h4>Decitabine is a deoxycytidine nucleoside derivative inhibitor of DNA-methyltransferases, which has been studied extensively and is approved for myelodysplastic syndrome in adults but with less focus in children. Accordingly, we conducted a phase 1 multicenter, randomized, open-label study to evaluate decitabine pre-treatment before standard induction therapy in children with newly diagnosed AML to assess safety and tolerability and explore a number of biologic endpoints.<h4>Re ...[more]

PMID: 29034009

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Project description:Purpose: Decitabine is a deoxycytidine nucleoside derivative inhibitor of DNA-methyltransferases indicated for treatment of myelodysplastic syndrome (MDS). Laboratory evidence shows that pretreatment of AML cell lines can sensitize leukemia cells to chemotherapy and inhibit clonogenic potential. We conducted a randomized study of decitabine when used as priming before standard induction therapy in children with newly diagnosed acute myelogenous leukemia (AML) to evaluate the safety, pharmacokinetics, and any potential early efficacy signal. Exploratory analyses of genomic methylation and RNA expression patterns and minimal residual disease (MRD) were included to elucidate possible biological mechanisms. Methods: This multicenter, randomized, two-arm, open-label study enrolled children ages 1-16 with newly diagnosed de novo AML to either Arm A: daunorubicin, cytarabine, etoposide preceded by a 5-day course of decitabine (experimental arm) or Arm B: daunorubicin, cytarabine, etoposide (control). Following completion of induction therapy, subsequent post-induction treatment was given at the treating physician’s discretion. Patients were monitored for adverse events and samples were collected for PK/PD and biologic analyses. Results: Twenty patients, ages 1-16 years (median 9.4 yrs in both Arms) were treated (10 per Arm). Eighteen of 20 enrolled subjects completed the prescribed treatment. All subjects experienced neutropenia and thrombocytopenia as is expected during AML induction chemotherapy. The most common grade 3 and 4 non-hematologic adverse events observed were caecitis, 2 (20%) subjects in Arm A and 0 (0%) subjects in Arm B; decreased appetite, 3 (30%) subjects in Arm A and 0 (0%) subjects in Arm B; and hypophosphatemia, 2 (20%) subjects in Arm A and 0 (0%) subjects in arm B. One subject in Arm A had appendicitis and colon perforation on Day 6 that led to study discontinuation; the cause was later determined to have been leukemic infiltrate of the bowel wall. Two subjects died (both in Arm A), one of necrotic bowel, pseudomonas sepsis and multisystem organ failure 6 months after study participation and one patient 5 months following study treatment from multisystem organ failure as a complication of stem cell transplant. Plasma concentrations of decitabine showed PK values (mean+SD) of Cmax, 281+113 ng/mL, AUC0-∞, 198+65.3 ng*h/mL, CL, 156+94.6 L/h, Vdss 109+70 L, t1/2 0.48+0.060 h, and median tmax 0.93 h. Overall CR/CRi by morphology was similar between the two treatment arms (92% for the control arm and 100% for the experimental arm). MRD at Day 30 post induction therapy was lower in the control group compared to the decitabine group (67% vs 85% MRD-negative). Changes in DNA epigenetic and RNA expression patterns demonstrated distinct differences involving selective cellular pathways between the two groups of patients comparing diagnostic to day 30 bone marrow samples. Conclusions: This first-in-pediatric trial of epigenetic priming in patients with newly diagnosed AML demonstrates that decitabine pre-treatment followed by standard combination chemotherapy is well tolerated in children with newly diagnosed AML. Morphologic complete responses were similar in both treatment arms. MRD at Day 30 following induction therapy suggests a deeper remission in patients receiving decitabine. No differences were observed between treatment arms in hematologic toxicities although decitabine-treated patients were noted to have more gastrointestinal toxicities, anorexia and hypophosphatemia. Decitabine PK parameters in children were consistent with known adult PK profiles. Molecular changes associated with decitabine pretreatment may be important in the sensitization of clonogenic AML cells. Pre-treatment with decitabine may represent a therapeutic option for use in pediatric AML, when epigenetic modification is a desired focus for treatment.

Project description:Background: Most children and adolescents infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop a mild coronavirus disease 2019 (COVID-19) that usually does not require medical intervention. However, a small proportion of pediatric patients develop a severe clinical condition, Multisystem Inflammatory Syndrome in Children (MIS-C). The involvement of epigenetics in the control of the immune response and viral activity prompted us to carry out an epigenomic study to uncover target loci regulated by DNA methylation that could be altered upon the appearance of MIS-C. Methods: Peripheral blood samples were recruited from 43 confirmed MIS-C patients with a median age of 7.7 years, most of whom were of West-Eurasian origin. Four or more organ systems were involved in the majority of patients. 69 non-COVID-19 pediatric samples and 15 COVID-19 pediatric samples without MIS-C were used as controls. The cases in the two groups were mixed and divided into discovery (MIS-C = 29 and non-MIS-C = 56) and validation (MIS-C = 14 and non-MIS-C = 28) cohorts, and balanced for age, gender and ethnic background. We interrogated 850,000 CpG sites of the human genome for DNA methylation variants. Findings: The DNA methylation content of 33 CpG loci was linked with the presence of MIS-C. Of these sites, 18 (54.5%) were located in described genes. The top candidate gene was the immune T-cell mediator ZEB2; and others highly ranked candidates included the regulator of natural killer cell functional competence SH2D1B; VWA8, which contains a domain of the Von Willebrand factor A involved in the pediatric hemostasis disease; and human leukocyte antigen complex member HLA-DRB1; in addition to pro-inflammatory genes such as CUL2 and AIM2. The identified loci were used to construct a DNA methylation profile (EPIMISC) that was associated with MIS-C in both cohorts. The EPIMISC signature was also overrepresented in Kawasaki disease patients, a childhood pathology with also a possible viral trigger, that shares many of the clinical features of MIS-C. Interpretation: We have characterized DNA methylation loci that are associated with the onset of MIS-C. The identified genes are likely contributors to the characteristic exaggerated host inflammatory response observed in these patients. The described epigenetic signature could also provide new targets for more specific therapies for the disorder.

Project description:The treatment of acute myeloid leukemia of older, medically non-fit patients still poses a highly unmet clinical need, and only few large, prospective studies have been performed in this setting. Given the established activity of hypomethylating agents such as 5-aza-2'-deoxycytidine (decitabine) in myelodysplastic syndromes and acute myeloid leukemia with 20-30% bone marrow blasts, we investigated whether this drug is also active in patients with more than 30% blasts.To evaluate the efficacy and toxicity of decitabine in patients over 60 years old with untreated acute myeloid leukemia ineligible for induction chemotherapy, 227 patients (median age, 72 years), many with comorbidities, adverse cytogenetics and/or preceding myelodysplastic syndrome were treated with this hypomethylating agent. During the initial decitabine treatment (135 mg/m(2) total dose infused intravenously over 72 hours every 6 weeks), a median of two cycles was administered (range, 1-4). All-trans retinoic acid was administered to 100 patients during course 2. Fifty-two patients who completed four cycles of treatment subsequently received a median of five maintenance courses (range, 1-19) with a lower dose of decitabine (20 mg/m(2)) infused over 1 hour on 3 consecutive days every 4-6 weeks.The complete and partial remission rate was 26%, 95% CI (20%, 32%), and an antileukemic effect was noted in 26% of patients. Response rates did not differ between patients with or without adverse cytogenetics; patients with monosomal karyotypes also responded. The median overall survival from the start of decitabine treatment was 5.5 months (range, 0-57.5+) and the 1-year survival rate was 28%, 95%CI (22%,34%). Toxicities were predominantly hematologic.Decitabine is well tolerated by older, medically non-fit patients with acute myeloid leukemia; myelosuppression is the major toxicity. The response rate and overall survival were not adversely influenced by poor-risk cytogenetics or myelodysplastic syndrome. Because of these encouraging results, randomized studies evaluating single-agent decitabine versus conventional treatment are warranted. The study is registered with the German Clinical Trials Registry, number DRKS00000069.

Project description:The aim of this study was to examine whether decitabine priming prior to low-dose chemotherapeutic regimens could improve outcomes in patients with myelodysplastic syndromes-refractory anemia with excess of blasts (MDS-RAEB).The current retrospective analysis included all MDS-RAEB patients receiving idarubicin/cytarabine (IA) or aclacinomycin/cytarabine (AA), with or without decitabine priming during a period from February 2010 to May 2015. Treatment response and toxicity were compared between patients receiving decitabine priming and those who did not. A panel of 6 MDS-related genes was examined using bone marrow specimens.A total of 81 patients were included in the analysis: 40 received decitabine priming prior to chemotherapy (decitabine priming group). The median follow-up was 10.9 months (IQR: 6.2-21.9). The rate of overall response (OR) and complete remission (CR) was significantly higher in the decitabine priming group than in the chemotherapy group (OR: 75.0 vs. 51.2%, p?=?0.027; CR: 55.0 vs. 29.3%, p?=?0.019). Overall survival (OS) did not differ significantly between the two groups (19.5 vs. 14.7 months, p?=?0.082). In a subgroup analysis that included only patients at <?60 years of age, the CR rate in the decitabine priming group was significantly higher than in the chemotherapy group (65.5 vs. 31.0%, p?=?0.009). Survival benefit of decitabine priming was apparent in patients at <?60 years of age (22.4 months with 95% CI of 6.7-38.1 vs. 14.7 months with 95% CI of 11.4-18.0 months in the chemotherapy group, p?=?0.028), patients with intermediate and unfavorable karyotypes (22.4 months with 95% CI of 15.1-29.7 vs. 11.9 months with 95% CI of 4.0-19.8 months in the chemotherapy group, p?=?0.042), and patients with mutated splicing factor genes (35.3 months with 95% CI of 21.4-49.2 vs. 17.8 months with 95% CI of 13.8-21.8 months in the chemotherapy group, p?=?0.039). Grade 3-4 hematological and non-hematological toxicities were not significantly different between the two groups.Decitabine priming prior to low-dose chemotherapy could improve treatment responses in patients with MDS-RAEB.

Project description:BackgroundElucidation of the genetic mechanisms underlying treatment response to standard induction chemotherapy in AML patients is warranted, in order to aid in risk-adapted treatment decisions as novel treatments are emerging. In this pilot study, we explored the treatment-induced expression patterns in a small cohort of AML patients by analyzing differential gene expression (DGE) over the first 2 days of induction chemotherapy.MethodsBlood samples were collected from ten AML patients at baseline (before treatment initiation) and during the first 2 days of treatment (Day 1; approximately 24 h, and Day 2; approximately 48 h after treatment initiation, respectively) and RNA was extracted for subsequent RNA sequencing. DGE between time points were assessed by pairwise analysis using the R package edgeR version 3.18.1 in all patients as well as in relation to treatment response (complete remission, CR, vs non-complete remission, nCR). Ingenuity Pathway Analysis (Qiagen) software was used for pathway analysis and visualization.ResultsAfter initial data quality control, two patients were excluded from further analysis, resulting in a final cohort of eight patients with data from all three timepoints. DGE analysis demonstrated activation of pathways with genes directly or indirectly associated with NF-κB signaling. Significant activation of the NF-κB pathway was seen in 50% of the patients 2 days after treatment start, while iNOS pathway effects could be identified already after 1 day. nCR patients displayed activation of pathways associated with cell cycle progression, oncogenesis and anti-apoptotic behavior, including the STAT3 pathway and Salvage pathways of pyrimidine ribonucleotides. Notably, a significant induction of cytidine deaminase, an enzyme responsible for the deamination of Ara-C, could be observed between baseline and Day 2 in the nCR patients but not in patients achieving CR.ConclusionsIn conclusion, we show that time-course analysis of gene expression represents a feasible approach to identify relevant pathways affected by standard induction chemotherapy in AML patients. This poses as a potential method for elucidating new drug targets and biomarkers for categorizing disease aggressiveness and evaluating treatment response. However, more studies on larger cohorts are warranted to elucidate the transcriptional basis for drug response.

Dataset Information

A multicenter, randomized study of decitabine as epigenetic priming with induction chemotherapy in children with AML.

Publications

A multicenter, randomized study of decitabine as epigenetic priming with induction chemotherapy in children with AML.

Similar Datasets

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